A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

Zhang, W.; Winder, Thomas; Ning, Yan; Pohl, Alexandra; Yang, Dongyun; Kahn, Michael; Lurje, Georg; LaBonte, Melissa J.; Wilson, Peter M.; Gordon, Michael A.; Hu‐Lieskovan, Siwen; Mauro, David; Langer, Christiane; Rowinsky, Eric K.; Lenz, Heinz‐Josef

doi:10.1093/annonc/mdq315

Cited by 116 publications

(101 citation statements)

References 28 publications

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“…Unsurprisingly, let-7b and let-7e are downregulated in HCT-116 after cetuximab treatment. The members of let-7 family are known to target K-ras and, recently, their involvement in cetuximab response has been reported (30). After cetuximab treatment, in resistant CRC cell lines, the signaling downstream of K-ras remains activated.…”

Section: Discussionmentioning

confidence: 99%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P < 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P < 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.

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Section: Discussionmentioning

confidence: 99%

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Ragusa¹,

Majorana²,

Statello³

et al. 2010

Molecular Cancer Therapeutics

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“…Germline SNP (rs61764370) has been recently extensively studied in relation to several types of cancer, especially in connection with associated risk, prognosis, and/or treatment response/resistance to therapy [1][2][3][4][5][6][7][8][9][10][11] . The let-7 family of miRNAs has been found to play an important role in tumorigenesis by regulating the expression of multiple oncogenes, including KRAS.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

Uvírová¹,

Šimová²,

Kubova³

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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, Petr Dite a,bAims. A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours. Methods. DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method. Results. The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples. Conclusions. Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6 genotype in colorectal cancer and NSCLC has not been established.

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“…As reported in previous papers, through their interactions with intracellular signaling networks, miRNAs can change cell proliferation, apoptosis and metastasis (Wu et al, 2011). Despite the growing knowledge about the likely role of miRNA in diagnosis (Huang et al, 2010;Link et al, 2010), prognosis (Diaz et al, 2008) and response to treatment of (Nakajima et al, 2006;Zhang et al, 2011) CRC, the data is still controversial and the association between miRNAs and CRC warrants further investigation.…”

Section: Discussionmentioning

confidence: 92%

microRNA Expression Profile in Patients with Stage II Colorectal Cancer: A Turkish Referral Center Study

Tanoğlu¹,

Balta²,

Berber³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

Abstract: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

Cited by 116 publications

References 28 publications

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Specific Alterations of MicroRNA Transcriptome and Global Network Structure in Colorectal Carcinoma after Cetuximab Treatment

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population

microRNA Expression Profile in Patients with Stage II Colorectal Cancer: A Turkish Referral Center Study

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